6-methyl-3-oxo-4, 7-dienic steroids



compounds.

t Y 3,176,010 6-METHYL-3-OX0-4J-DIENTC srnaorns George Cooley, Bernard Ellis, and Vladimir Petrow,

London, England, assignors to The British Drug Houses Limited a No Drawing. Filed Mar. 19, 1963, Ser. No. 266,198

Claims priority, application Great Britain, Mar. 22, 1%2,

11,106/62 8 Claims. (Cl. 260-397 .4)

This invention is for improvements in or relating to organic compounds and has particular reference to 6- niethyl-3-oxo-4J-dienic steroids of the androstane and pregnane series, which group of compounds has hitherto not'been known in the art.

It is an object of the present invention to provide novel 6-methyl-3-oxo-4,7-dienic steroids of the androstane and pregnaneseries, including the general Formula 1 below which compounds are of value on account of their biological properties such for example, as anabolic, androgenic, ovulation inhibiting, claudogenic properties or as intermediates in the preparation of compounds with useful biological, hormonal or antihormonal properties.

The present invention provides the following specific novel steroidal compounds! 17a acetoxy 6 methylpregna 4,7 diene 3,20-

dione and 17a acetoxy 6,161 dimethylpregna 4,7-

diene-3,20-dione, which are of value on account of their hormonal properties. Thus, for example, the compounds have a favourable ovulation inhibiting/progestational index which renders them of value in, for example, the control of fertility in domestic animals.

6-methylandrosta-4,7-diene-3,17-dione, which is of value on account of its anabolic/ androgenic properties and as an intermediate for the preparation of hormonally active may beconverted into the corresponding 6-methyl-7-dehydrotestosterone which is of value on account of its anabolic/androgenic index.

17 acetoxy 21 fluoro 6 methylpreg na 4,7- diene 3,20-dione, 17o 21-diacetoxy-o-methylpregna-4,7- diene-3,20-dione and 16a,l7a-diacetoxy-6-methylpregna- 4,7-diene-3,2 -dione possess antifertility properties.

, 17B acetoxy 6,17a dimethylandrosta 4,7 dien 3- one and 17B-acetoxy-l7ot-ethynyl-6-methy1androsta-4,7-

- dien-3-one possess anabolic/ androgenic properties.

Accordingto the present invention there is provided a process for the preparation of 6-methyl-3-oxo-4,7-dienic Thus, for example, by prior art methods used for the conversion of 6-methylandrost-4-ene-3,17- dione into the corresponding 6a-methyltestosterone, it

United. States i 3,176,010 Patented Mar. 30, 1965 where R is an alkyl or alicyclic radical containing not more than 7 carbon atoms with an acidic reagent which will regenerate the 3-oxofunction. The acidic reagent for example, may comprise acetic acid, oxalic acid, or hydrochloric acid.

In carrying the process of the invention into effect, the 6-methyl-3,5,7-trienic-3-enol ether of Formula '11 may be converted into the 6-methyl-3-oxo-4,7-diene of Formula I t by treating it with, for example, aqueous acetic acid, under appropriate experimental conditions. When aqueous acetic acid is used, the enol ether (II) may be dissolved in a convenient volume of acetic acid at a temperature which may bein the region of l00 C., and the solution diluted with water,added portion wise over a period of 201- minutes, in suflicient quantity to cause separation of the crude 6-methyl-3-oxo-4,7-dienic product (I). The temperature may be maintained'in the region of 100* C. throughout this operation. Thereafter the 30 product may be collected by filtration, and purifiedby techniques well-known to those skilled in the art. In some cases, the steroidal product fails to separate from the reaction mixture inthe solid or crystalline state. A large excess of water may then be addedto the reaction mixture,tand the product isolated by. extraction with asuitable organic solvent and subsequently purified;

The process of the inventionmay be applied to derivatives of the androstane series including the general Formula II and which may be additionally/ substituted by hydroxyl or acyloxy groups, for example at position C and/or C by lower alkyl, alkenyl, alkynyl groups or halo derivatives thereof, for example at position C and by oxo-g'roups, or functional derivatives thereof, forex ample at C i The process. of the invention may also be applied to derivatives of the pregnane series includingthe general Formula II and which may be additionally substituted by steroids of the androstane and pregnane series, including the general formula which process comprises treating a 6-methyl-3,5,7-trienic- 3-enol etherincluding the general formula Me (I) R is H or Me where R is H, Cl, F, Br, OH (OAcyl) R is H, Me, F, OH (OAcyl) OH(OAoyl) where R is H, alkyl, alkenyl, alkynyl, aryl or alkaryl, up to 8 carbon atoms; haloalkynyl, trifluoromethylalkynyl, dialkynyl carboxylic acids containing from 1 to 12 carbon atoms inclusive, for examplea saturated Straight chain aliphatic acidsuch as acetic, propion-ic, butyric, valeric, hexanoic; lauric; a saturatedbranched-chain aliphatic acid, e.g. trimethylacetic, isobutyric, isovaleric, a cycloaliphatic saturated acid,e.g. cyclohexane carboxylic acid, ,B-cyclopen- 'tanepropionic acid; an'alkaryl'acid, e.g. phenyl acetic, 2i-phenylpropionic, o-, mand p-toluic; a saturated dibasic *acid (which maybe. converted into water soluble, e,g. "sodium salts), e.g. succinic, adipic; a mono basic unsaturated acid, e.g. acrylic, crotonic, undecylenic, propiolic, cinnamic; a dibasic unsaturated acid '(Which can :becon- *verted into water soluble e.g. sodium salts), e.g. maleic and citraconic. Y i Theinitial materials employed in the process of the present invention may be prepared according to a process described in our 'copending application No. 227,706, filed 011 October 2, 1962, now US. Patent No. 3,153,060, in which the appropriate 3-oxo-6 methyl-4,6-dienic derivative is submitted to enol etherification by reaction with an aliphatic or alicyclic alcohol (containing up to 7 carbon atoms) or with an orthoformate ester thereof in the presence of a catalytic quantity of H+ ions.

The initial material employed in Example 2 of the I present invention was prepared in the following way:

7 6-methylandrosta-4,6-diene 3,17 dione (Ellis, Kirk, Petrow, Waterhouse and Williamson, J. Chem. Soc., 1960, 2828) (6; g.) in dry' benzene (100 ml.) was treated with methyl orthoformate (4 ml.) methanol (4 ml.) and toluene-p-sulphonic acid (200 mg), and the mixture heated under reflux for 2 hours. After the addition of pyridine (4 ml.), the cooled mixture was washed with water, dried and the solvents removed. Methanol (20 ml.) was added to the residue, and then evaporated in vacuo. This process wasr'epeated to ensure complete removal of benzene. crystallisation of the residue from acetone containing a trace of pyridine gave 3,17,l7-tri- 3 3,1 2916,1619,1620,13920m.- 1134,832 cutpared as'follows:

The initial material employed in Example 4 was prepared as follows:

17ot acetoxy 21 fluoro 6 methylpregna 4,6- diene-3,20-dione (Sollman, Elton and Dodson, J. Amer. Chem. Soc., 1959, 81, 4435) (3 g.) in dry benzene ml.) was treated with triethylorthoformate (2 ml.) ethanol (2 ml.) and toluene-p-sulphonic acid (100 mg.) and the mixture heated under reflux for 3 /2 hours. Pyridine (1 ml.) was added to the cooled mixture, which was then washed and dried. After removal of the solvents in vacuo, the residue was purified from ethanol containing a trace of pyridine to give 17u-acetoxy-3-ethoxy-2l-fluoro- 6-methylpregna-3,5,7-trien-20-one, needles, 75 321 m (6 19,000),

1736, 1718, 1648 and 1616 emf max.

The initial material employed in Example 5 was pretreated with methyl orthoformate (1.5 ml.), methanol (1.5 ml.) and toluene-p-sulphonic acid (75 mg), and the mixture heated under reflux for 2 /2 hours] After the addition of pyridine (2 ml.), the cooled mixture was washed, dried, and the solvents removed. Crystallisation of the residue from aqueous acetone containing a trace of pyridine gave 17 ,21-diacetoxy-3-methoxy-6methylpregna-3,5,7-trien-20-one, needles, A a 322 -m;;. (6, 19,500), g V I *1738, 1720, 1647 and 1617 cmf max.

The initial material employed in Example 6 was pre- A solution of 6,17a-dimethyl-17,8-hydroxyandrosta-4,6-

dien-3-one (Ellis, Kirk, Petrow, Waterhouse and Williamson, J. Chem. Soc., 1960, 2828) (5 g.) in acetic anhydride (20 ml.) and pyridine (20 ml.) was heated-for 4 hours under reflux. Themixture was poured into water, and the product purified by crysallisation to give 171?- acetoxy-6,17a-dimethylandrosta-4,6-dien 3 -one, )t 290 mu. (6, 23,500). This compound (3 g.) in dry benzene (60 ml.) was treated with methyl 'orthoformate (2.5

ml.), ethanol (2.5 ml.) and toluene-p-sulphonic acid (130 The residue was purifiedfrom aqueous methanol containing a trace .of pyridine. to give .17fl-acetoxy-6,l7qt-dimethyl-3-methoxyandrosta-3,5,7-triene A 320 1I1,u (6, 19,450),

231 1730, 48 and 1610mm.- The initial material employed in Example 7-was 3-one (Ellis, Kirk, Petrow, Waterhouse and Williamson,

J. Chem. Soc., 1960, 2828) (4.5 g.) in acetic anhydride (20 m1.) and pyridine (20 ml.) was heated under reflux for 3% hours. The product obtained onpouring the mixture into water was purified from aqueous ethanol to give 17fi-acetoxy 17uethynyl-6-methylandrosta-4,6- dien-3-one, A 289 III/.0 (6, 22,600). This compound (3 g.) in dry benzene (50 ml.) was treated with ethyl orthoformate .(2 ml.) ethanol (2 ml.) and toluene-p-sulphonic acid mg.) and the mixture heated under reflux for four hours. The mixture was cooled, pyridine (1 ml.) was added, and after being washed and dried, the solvents were removed in vacuo. Crystallisation of the residue from aqueous ethanol containing a trace of pyridine gave 17B-acetoxy-3-ethoxy-17m-ethynyl-6-methylandrosta-3,5,7-triene, A 321 m (6, 19,050),

' 355? 1729, 1649 and 1620 (mte) airy" .tone. separated in prisms, M.P. 240 to 243 C. [01],; 6 (0.,

The initial material employed in Example 8 was prepared as follows:

16u,17a-diacetoxy 6 methylpragna 4,6 diene-3,20- dione (Ellis, Hall, Petrow and Williamson, J. Chem. Soc., 1962, 22) (2 g.) in dry benzene (30 ml.) was treated with methyl orthoformate (1.5 ml.), methanol (1.5 ml.) and tolune-p-sulphonic acid (50 mg.), and the mixture refluxed for 3 hours. After addition of pyridine, (1 ml.), the cooled mixture was washed, dried, and the solvent removed in vacuo. The residue was purified from methanol containing a trace of pyridine to give 16u,17x-diacetoxy-3-methoxy-6-methylpregna-3,5,7-trien-20-one, A 323 m (e, 19,450),

721312 1720, 1648 and 1616 cmf Following is a description by way of example of methods of carrying the inventioninto effect.

A solution of 17a acetoxy-3-ethoxy-6-methylpregna-3,

5,7-trien-2 0-one-(2 g.) in acetic acid (75 ml.) and water (1 ml.) was heated for minutes on the steam-bath.

. Thereafter, water was added portionwise during 20 minutes, with continued heating of the mixture, until crystallisation of the product occurred. When cool, the crystals were collected by filtration, washed and dried. A solution in benzene was filtered through a small column of alumina, to give material which crystallised from ace- 1711 i acetoxy-6-methylpregna-4,7-diene-3,20-dione 0.38 in chloroform), ,Amax, 23 7 -238m,u. (e, 15,420),

A solution at 3,17,l7-trimethoxy-G-methylandrosta- 3,5,7-triene (1.6 g.) in aceticacid (70 1111.) and water (3 ml.) was heated for 1 0 minutes on the steam bath. Thereafter, water (200 ml.) was added gradually during 20 minutes, with continued heating of the mixture, until the product separated in an oily condition. More water was added to the cooled mixture, the product isolated with ether, and its benzene solution filtered through a short column of alumina. Removal of the solvent gave a residue which was purified from methanol. 6-methy1- androsta-4,7-diene-3, l7-dione separated in prismatic needles, M.P. 157 to 160 C., [u] +98 C., 0.68 in chloroform), A 237.5 nm (6 14,800),

,33 2964, 1745, 1681, 1e20, 1453 and 1373 @m.

. during 2 0 minutes, with continued heating of the mixture,

17u-acetoxy-6, 16a-dimethyl-3-ethoxypregna-3 ,5 ,7-trien- 20-one (3.0 g.) in warm acetic acid ml.) was treated with water (1.5 ml.) and the mixture heated for 10 minutes on the steam-bath, Thereafter, water (200 ml.) was added gradually during 20 minutes. with continued heating of the mixture. 'After being thoroughly cooled, the product was filtered off and washed neutral.

It was then chromatographed on alumina; employing. benzene as eluant to givematerial which was fractionally crystallised front-acetone. 17cc acetoxy-6,16a-din1ethy1pregna-4,7- diene-3,20 dione separatedas cubes, M.P. 172 to 175 C.

.EXAMPLE. 4 I 1 7 a-acetoxy -21 -flu0ro-6-m ethylpregna- 4,7-diene-3,20-dione A solution of 17a-acetoxy- 3-ethoxy- 2l-fluoro-6-methylpregna-3,5,7-trie11-20 one (1.5 g.) in acetic acid (60 m1.) and water (2 ml.) was heated for 10 minutes on the steam bath- Thereafter, water ml.) was added gradually until, the product separated, It was isolated withj ether, and its benzene solution filtered through a short column of alumina. Removal of the solvent gave a residue which was purified frorn methanol. l7a-aoetoxy 2l-fluoro-fimethylpregna-4,7-diene-3,20-di0ne separated in needles, max. 238 l i l 912. 1? 1743, 1720, 1e71, 1618 cmf EXAMPLE 5 l701,21-diacetoxy-6-methylpregna-4,7-diene-3,20-dione until precipitation of the product was complete. It was collected, washed and repeatedly crystallised from aque- 7 ous ethanol to give 17oi,2'lkdiacetoxy-6-methylpregna-4,7- diene-3,20-dione, needles, 21 239m (12, 15,850),

313 15 1742, 1720, 1e74, 1619 cat- EXAMPLE 6 l y- J 7 v-dimethylandrosIa-4,7-dien-3-one OAe '--Me Me I I ll Ii 0: 1

A solution of 17/3-acetoXy-6,l7a-d1imethyl-3-methoxyandrosta-3,5,7-tniene (300 mg.) in methanol (.15 ml.) at 40 C. was treated with one dropIof concentrated hydrochloric acid. Two minutes later, the mixture was poured into water and the product isolated with ether and purified by crystallisation. 17,8-acetoxy 6,lfiawdimethylandrosta-4,

.7-dien-3-one formed. Crystals, 238 mu (11,15,200),

- 7 EXAMPLE 7 7134166107074 7 ynyl6-methylandrosta- 4,7-'dien-3-0ne OAc a A solution of 1 175-acetoxy-3-ethoxy- 17oieethyny1-6-methylandrosta-3,5,7-triene (0.5 g.) in methanol (25' ml.) at 35 C. was treated with one drop of concentrated hydrochloric acid, and the mixture was poured into water. The product was isolated with ether, and crystallised to give 175 acetoxy 17a-ethynyl 6 methylandr0sta4,7-dien-3- one, 71 238.5 m, (6, 15,650),

0014 max.

2240, 1738, 1670,1619 cmr EXAMPLE 8 1 60,] 7 a-diacetoxy-6-methylpregna-4,7-diene-3,20-dione 16a,17m-diacetoxy-3-methoXy-6 -rnethylpregna 3,5,7- trien-ZO-one (1 g.) in acetic acid (35 ml.) and water (1 ml.) was heated for minutes on the steam bath. The mixture was poured into Water and the product isolated with ether-rand crystallisedfrom aqueous ethanol.

17a diacetoxy 6 methylpregna 4,7 diene-3,20-dione formed needles, A 238.5 nm (6, 14,950),

C014 1740, 1719, 1e72, 1620 ant- We claim: g 1. A 6-methyl-3-0Xo-4,7-dienic steroid selected from the group consisting of wherein R has the definition given above, and R is selectedfrom the group consisting of hydrogen, lower alkyl and lower alkynyl.

2. 17a-acetoxy-6-methylpregna-4,7-diene-3,20-dione.

3. l7a-acetoxy 6,1600- dimethylpregna-4,7-diene-3,20- dione.

4. 17a-acetoxy-21-fluoro 6 methylpregna-4,7-diene- 3,20-dione.

5. 17a,21-diacetoxy'- 6 methylpregna-4,7-diene-3,20-

dione.

-6. 17fi-acetoXy-6,17a-dimethylandrosta 4,7 dien-3- one. 7

7. 17B-acetoxy a ethynyl 6 methylandrosta-4,7- dien-3-one.

s. 16a,17 x-diaceto ry 6 methylpregna-4,7-diene-3,20-

dione.

, References Cited by the Examiner UNITED STATESPATENTS 2/60 Dauben et al. 260-43955 FOREIGN PATENTS 4/54 Great Britain.

OTHER REFERENCES Ercoli et al.: J.'A.C.S. 75, pp. 650-653 (1953). Fieser et al.: Natural Products Related to 'Plienanthrene, 3 rd' ed., 1949, pp. 371472, ReinholdPub.'Co., N.Y.

LEWIS GOTITS, Primary Examiner. 

1. A 6-METHYL-3-OXO-4,7-DIENIC STEROID SELECTED FROM THE GROUP CONSISTING OF 